Pulmonary oxygen toxicity is associated with histological evidence of polymorphonuclear neutrophil (PMN) infiltration into lung parenchyma. What guides infiltration of these cells is unknown. A number of chemoattractants for PMN have been documented including interleukin-8 (IL-8), a cytokine released by alveolar macrophages (AM) and other cell types. The purposes of this study were to 1) determine whether human AM and the histiocytic U937 cell line release IL-8 in response to hyperoxia, 2) assess whether hyperoxia results in increased IL-8 steady-state mRNA levels in U937 cells and 3) establish whether dexamethasone could attenuate noted effects of hyperoxia. Our study shows that hyperoxia stimulates human AM and U937 cell release of IL-8. Hyperoxia also increases IL-8 mRNA levels in U937 cells. IL-8 released in response to hyperoxia by AM was biologically active as evidenced by ability to induce PMN chemotaxis. A polyclonal antibody to IL-8 partially attenuated this chemotactic activity. Finally, dexamethasone at concentrations of 10 microM, 1 microM, and 100 nM markedly reduced hyperoxia-induced IL-8 release and mRNA synthesis by U937 cells. We conclude that IL-8 may be important in the pathogenesis of pulmonary oxygen toxicity and that therapeutic concentrations of dexamethasone can suppress production of this cytokine.

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Infection with influenza virus is commonly associated with polymorphonuclear neutrophil (PMNL) dysfunction and consequent secondary bacterial pneumonia. A recently isolated human-derived protein that inhibits PMNL chemotaxis and oxidant production shows a striking homology to the influenza A nucleoprotein. In the present study, the effects of purified influenza A nucleoprotein on PMNL chemotaxis, oxidant production, degranulation, and calcium homeostasis were studied. Results of the study demonstrate that purified nucleoprotein inhibits PMNL chemotaxis as well as superoxide production. In addition, purified nucleoprotein induces a rise in PMNL cytosolic calcium concentration in a manner similar to that demonstrated for crude influenza A lysates. In contrast, no difference in FMLP-stimulated PMNL elastase or beta glucuronidase release was noted after exposure to nucleoprotein. These studies suggest that the influenza A nucleoprotein may account for some of the neutrophil defect associated with cellular infection by this virus.

Reactive oxygen species can directly damage tissue. In this setting, amplification of tissue damage also occurs through infiltration of inflammatory cells either acutely or chronically. Several recent studies suggest that reactive oxygen species stimulate production of certain chemokines, which are potent chemoattractants for inflammatory cells. In the present study, we examined whether oxidants, generated by the combination of xanthine and xanthine oxidase (X/XO), alter chemokine production by monocytes and U937 cells. Our findings demonstrate that X/XO stimulates monocytes, but not U937 cells, to produce increased amounts of interleukin-8 (IL-8) and monocyte chemoattractant protein. This effect is attenuated by pretreatment with dimethylsulfoxide (DMSO), a scavenger of hydroxyl radicals, but is not affected by superoxide dismutase or catalase. In contrast, X/XO-induced cytotoxicity, evidenced by lactate dehydrogenase release, is mediated primarily by hydrogen peroxide, as catalase reverses this effect. Finally, exposure to X/XO causes an increase in nuclear factor kappa B (NF-kappaB), and this effect is attenuated by DMSO. These studies suggest that reactive oxygen species can induce production of molecules that amplify inflammation through attraction of inflammatory cells. It appears the hydroxyl radical is the principal oxidant species involved in stimulation of chemokine production.